Background The APOE {varepsilon}4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE {varepsilon}4 allele, those who are heterozygous for the allele, and noncarriers is unknown. Methods Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE {varepsilon}4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE {varepsilon}4 allele, using a mixed model for longitudinal change with age. Results We analyzed 815 subjects: 317 APOE {varepsilon}4 carriers (79 who were homozygous for the APOE {varepsilon}4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele-dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status. Conclusions Age-related memory decline in APOE {varepsilon}4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.

DOI: 10.1056/NEJMoa0809437
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